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2006 Grant - Gong

Role of Ubiquitin-C-Terminal Hydrolase L1 in Alzheimer's Disease

Bing Gong, M.D. Columbia University Medical CenterNew York, New York

2006 New Investigator Research Grant

Alzheimer's disease is characterized by the aggregation of proteins into insoluble clumps called plaques and tangles. Some of these aggregates contain ubiquitin, a small protein marker that normally flags unwanted proteins for degradation. The appearance of these ubiquitin-tagged proteins in Alzheimer-related aggregates has led to the hypothesis that routine mechanisms for eliminating unwanted or damaged proteins are not functioning properly in the brains of people with the disease. Indeed, there is evidence that the proteasome, a type of cellular garbage disposal that degrades ubiquitinated protein, is not functioning at full capacity in people with Alzheimer's. However, scientists are unsure whether a weakened proteasome contributes to the accumulation of these aggregates or whether the aggregates clog up the proteasome.

Bing Gong, M.D., plans to address this by measuring how the protein degradation process affects pathology in genetically altered mice that develop an Alzheimer-like disorder. His lab has preliminary data to suggest that boosting levels of ubiquitin-C-terminal hydrolase (Uch-L1), a key enzyme in the ubiquitin-proteasomal degradation system, can help prevent communication problems between neurons in the brains from these animals. Loss of cell-to-cell communication contributes to the learning and memory deficits experienced by people with Alzheimer's.

Gong and his team plan to test whether injecting the same protein into the brains of these animals can also prevent the accumulation of amyloid plaques. The researchers plan to try both a one-week and a three-month treatment with Uch-L1. In both cases they will also determine if the animals show any improvement in neuronal function and cognition. The findings could suggest new avenues to explore for finding disease-modifying treatments for Alzheimer's.